Graves Disease: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Graves Disease. Trace genetic associations through variants, genes, and proteins …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Graves Disease. Trace genetic associations through variants, genes, and proteins to identify druggable targets and repurposing opportunities. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 1: DISEASE IDENTIFIERS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find all database identifiers for Graves Disease: MONDO, EFO, OMIM, Orphanet, MeSH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 2: GWAS LANDSCAPE ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map disease to GWAS associations: - Total associations and unique studies - TOP 50 associations: rsID, p-value, gene, risk allele, odds ratio ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 3: VARIANT DETAILS (dbSNP) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ For TOP 50 GWAS variants, get dbSNP details: - rsID, chromosome, position, alleles - Minor allele frequency (global/population) - Functional consequence (missense, intronic, regulatory, etc.) Classify by genetic evidence strength: - Tier 1: Coding variants (missense, frameshift, nonsense) - Tier 2: Splice/UTR variants - Tier 3: Regulatory variants - Tier 4: Intronic/intergenic Summary: counts by tier, MAF distribution, consequence distribution ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 4: MENDELIAN DISEASE OVERLAP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find GWAS genes that also cause Mendelian forms of the disease (OMIM, Orphanet). Genes with BOTH GWAS + Mendelian evidence = highest confidence targets. List: Gene, GWAS p-value, Mendelian disease, inheritance pattern ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 5: GWAS GENES TO PROTEINS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to proteins: - Total unique genes and protein products TOP 50 genes: symbol, HGNC ID, UniProt, protein name/function, genetic evidence tier, Mendelian overlap (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 6: PROTEIN FAMILY CLASSIFICATION ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Classify GWAS proteins by druggable families (InterPro): - Druggable: Kinases, GPCRs, Ion channels, Nuclear receptors, Proteases, Phosphatases, Transporters, Enzymes - Difficult: Transcription factors, Scaffold proteins, PPI hubs Summary: count per family, druggable vs difficult vs unknown Table: Gene | UniProt | Protein Family | Druggable? | Notes ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 7: EXPRESSION CONTEXT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check tissue and single-cell expression for GWAS genes. Identify disease-relevant tissues/cell types for Graves Disease. Analysis: - Which tissues/cell types highly express GWAS genes? - Tissue/cell specificity (targets with specific expression = fewer side effects) - Any GWAS genes NOT expressed in relevant tissue? (lower confidence) Table TOP 30: Gene | Tissues | Cell Types | Specificity ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 8: PROTEIN INTERACTIONS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map protein interactions among GWAS genes (STRING, BioGRID, IntAct). Analysis: - Do GWAS genes interact with each other? (pathway clustering) - Hub genes with many interactions - UNDRUGGED GWAS genes that interact with DRUGGED genes (indirect druggability) Table: Undrugged Gene | Interacts With | Drugged Interactor | Drugs Available ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 9: STRUCTURAL DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check structure availability for GWAS proteins (PDB, AlphaFold). Structure availability affects druggability. Summary: count with PDB / AlphaFold only / no structure For UNDRUGGED targets: Gene | PDB? | AlphaFold? | Quality ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 10: DRUG TARGET ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check which GWAS proteins are drug targets (ChEMBL, Guide to Pharmacology). Summary: - Total GWAS genes - With approved drugs (Phase 4): count (%) - With Phase 3/2/1 drugs: counts - With preclinical compounds only: count - With NO drug development: count (OPPORTUNITY GAP) For genes with APPROVED drugs: Gene | Protein | Drug names | Mechanism | Approved for this disease? (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 11: BIOACTIVITY & ENZYME DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check bioactivity data for GWAS proteins (PubChem, BRENDA for enzymes). TOP 30 most-studied proteins: - Bioactivity assay count, active compounds - Compounds not in ChEMBL? (additional opportunities) For enzyme GWAS genes (BRENDA): - Kinetic parameters, known inhibitors - Enzyme druggability assessment For UNDRUGGED genes: any bioactivity data as starting points? ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 12: PHARMACOGENOMICS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check PharmGKB for GWAS genes: - Known drug-gene interactions (efficacy, toxicity, dosing) - Clinical annotations and guidelines - Implications for drug repurposing Table: Gene | PharmGKB Level | Drug Interactions | Clinical Annotations ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 13: CLINICAL TRIALS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Get clinical trials for Graves Disease: - Total trials, breakdown by phase TOP 30 drugs in trials: Drug | Phase | Mechanism | Target gene | Targets GWAS gene? (Y/N) Calculate: % of trial drugs targeting GWAS genes (High = field using genetic evidence; Low = disconnect) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 14: PATHWAY ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to pathways (Reactome). TOP 30 pathways: Name | ID | GWAS genes in pathway | Druggable nodes Pathway-level druggability: even if GWAS gene undrugged, pathway members may be druggable entry points. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 15: DRUG REPURPOSING OPPORTUNITIES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Identify drugs approved for OTHER diseases that target GWAS genes. Prioritize by: 1. Genetic evidence (Tier 1-4) 2. Mendelian overlap 3. Druggable protein family 4. Expression in disease tissue 5. Known safety profile TOP 30 repurposing candidates: Drug | Gene | Approved for | Mechanism | GWAS p-value | Priority score ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 16: DRUGGABILITY PYRAMID ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Stratify ALL GWAS genes into 6 levels. Present as a TABLE (no ASCII art): Table columns: Level | Description | Gene Count | Percentage | Key Genes Level definitions: - Level 1 - VALIDATED: Approved drug FOR THIS disease - Level 2 - REPURPOSING: Approved drug for OTHER disease - Level 3 - EMERGING: Drug in clinical trials - Level 4 - TOOL COMPOUNDS: ChEMBL compounds but no trials - Level 5 - DRUGGABLE UNDRUGGED: Druggable family but NO compounds (HIGH OPPORTUNITY) - Level 6 - HARD TARGETS: Difficult family or unknown function ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 17: UNDRUGGED TARGET PROFILES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Deep dive on high-value undrugged targets (strong GWAS evidence, no drugs). Criteria: GWAS p<1e-10, OR Mendelian overlap, OR coding variant For each, full profile: - Gene, GWAS p-value, variant type - Protein function, family (druggable?) - Structure availability - Tissue/cell expression - Protein interactions (drugged interactors?) - Why undrugged? (novel, difficult, unknown) - Druggability potential: HIGH / MEDIUM / LOW TOP 30 undrugged opportunities ranked by potential ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 18: SUMMARY ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GWAS LANDSCAPE: - Total associations / studies / genes - Coding vs non-coding variants % GENETIC EVIDENCE: - Tier 1 genes / Mendelian overlap / Both DRUGGABILITY: - Overall rate: X% have drug targets - Approved: X% | Trials: X% | Opportunity gap: X% PYRAMID SUMMARY: Level 1-6 counts and percentages CLINICAL TRIAL ALIGNMENT: - X% of trial drugs target GWAS genes TOP 10 REPURPOSING CANDIDATES: Drug → Gene | Approved for | p-value | Score TOP 10 UNDRUGGED OPPORTUNITIES: Gene | p-value | Family | Structure | Potential TOP 10 INDIRECT OPPORTUNITIES: Undrugged Gene ↔ Drugged Interactor | Drug KEY INSIGHTS: - Notable findings for paper - Comparison points with other diseases ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ FORMATTING ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ - Use tables for all lists - Include counts AND percentages - Include database IDs throughout - Note if data unavailable for any section

Structured Data Sources

This answer was generated using Claude Opus 4.5 + BioBTree MCP, querying 23 biological databases.

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, dbsnp, drugbank, efo, gtopdb, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb, pubchem_activity, reactome, string_interaction, uniprot
Generated: 2026-04-07 — For the latest data, query BioBTree directly via MCP or API.
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Graves Disease

GWAS-to-Drug-Target Druggability Analysis: Graves Disease

Section 1: Disease Identifiers

DatabaseIdentifierNameCross-references
MONDOMONDO:0005364Graves disease216 xrefs
EFOEFO:0004237Graves disease370 xrefs
MeSHD006111Graves Disease3,362 xrefs
HPOHP:0100647Graves disease31 xrefs
Orphanet424Familial hyperthyroidism (TSH receptor)148 xrefs
NoteSynonyms
Graves disease is primarily a complex autoimmune disorder. Orphanet 424 covers the related familial form caused by TSHR mutations. Direct OMIM phenotype entries for Graves disease map through TSHR (MIM:603372) and CTLA4 (MIM:123890) genes.
Basedow disease, Basedow's disease, exophthalmic goiter, Graves' hyperthyroidism, Parry disease, toxic diffuse goiter, Flajani-Basedow-Graves disease

Section 2: Gwas Landscape

Summary Statistics:

  • Total GWAS associations: 134
  • Unique GWAS studies: 23
  • Unique protein-coding genes: 41

TOP 50 GWAS Associations

RankrsIDP-valueGene(s)ChrStudy
1rs94698991×10⁻⁶⁸HLA-DPA16GCST90018847
2rs22730172×10⁻⁶⁷HLA-DPA26GCST90018627
3rs15212×10⁻⁶⁵MICA-AS16GCST001200
4rs49472964×10⁻⁵¹RNU6-1133P/C6orf156GCST001200
5rs121012612×10⁻³⁶TSHR14GCST90018847
6rs64576177×10⁻³³HLA-DQB16GCST001200
7rs3127298×10⁻²⁹CALM2P1/CASC1717GCST008365
8rs30872434×10⁻²⁶CTLA42GCST90018847
9rs121012617×10⁻²⁴TSHR14GCST001200
10rs38934642×10⁻²²TSBP1-AS16GCST001219
11rs48261988×10⁻²²P2RY10/GPR174XGCST90018847
12rs582660672×10⁻²⁰TSHR14GCST90479863
13rs115712972×10⁻¹⁷CTLA42GCST001200
14rs59128384×10⁻¹⁷GPR174XGCST90013683
15rs24766016×10⁻¹³PTPN22/AP4B1-AS11GCST90018847
16rs37619592×10⁻¹³FCRL31GCST001200
17rs12658833×10⁻¹³SLAMF61GCST90018847
18rs43130341×10⁻¹³RHOH4GCST001200
19rs110660153×10⁻¹⁵ALDH212GCST90018847
20rs110657833×10⁻¹⁵ACAD1012GCST90018627
21rs2295275×10⁻²⁰C1QTNF622GCST001984
22rs176891592×10⁻¹¹MAFTRR/LINC0122916GCST90018847
23rs108219441×10⁻¹¹ARID5B10GCST90018847
24rs7067792×10⁻⁶IL2RA10GCST005526
25rs15697232×10⁻¹²CD4020GCST90018847
26rs130931104×10⁻¹³LPP3GCST90018847
27rs729280387×10⁻⁹BACH26GCST90018847
28rs345442597×10⁻¹⁰UBASH3A21GCST90018847
29rs93571567×10⁻¹⁰CEP43/CCR66GCST90018847
30rs2317799×10⁻⁹STAT42GCST90018847

Section 3: Variant Details (Dbsnp)

Key Variant Characterization

rsIDChrPositionRef/AltMAF (gnomAD)ConsequenceGene
rs24766011113834946A/G,T0.066Missense/UTRPTPN22
rs30872432203874196G/A,T0.3693' regulatoryCTLA4
rs121012611480984885C/T0.377IntronicTSHR
rs1521631382927C/G,TCommonIntergenicHLA region
rs6457617632696074C/A,TCommonHLA regionHLA-DQB1
rs108219441062025330G/T0.662IntronicARID5B
Genetic Evidence Tier Classification
TierDescriptionCountPercentageKey Genes
Tier 1Coding variants (missense)37%PTPN22, TSHR
Tier 2Splice/UTR variants410%CTLA4, PTPN22
Tier 3Regulatory variants1229%HLA region, BACH2
Tier 4Intronic/intergenic2254%ARID5B, IL2RA, LPP
Notable: rs2476601 (PTPN22 R620W) is a well-established autoimmune risk variant with functional missense change.

Section 4: Mendelian Disease Overlap

Genes with GWAS + Mendelian Evidence

GeneGWAS P-valueOMIMMendelian DiseaseInheritance
TSHR2×10⁻³⁶603372Familial hyperthyroidism; HypothyroidismAD
CTLA44×10⁻²⁶123890ALPS type V (autoimmune lymphoproliferative)AD
PTPN226×10⁻¹³600716Susceptibility to autoimmune diseasesComplex
ClinVar Variants in GWAS Genes:
  • TSHR: 127+ ClinVar entries including pathogenic variants causing congenital hypothyroidism, familial hyperthyroidism
  • CTLA4: 100+ ClinVar entries including pathogenic variants causing CTLA4 haploinsufficiency syndrome (CHAI/LATAIE)

Highest Confidence Targets: TSHR, CTLA4, PTPN22 (convergent GWAS + Mendelian evidence)

Section 5: Gwas Genes To Proteins

Summary: 41 unique protein-coding genes → 41 UniProt proteins

TOP 30 GWAS Genes with Protein Information

GeneHGNC IDUniProtProtein NameEvidence TierMendelian
TSHRHGNC:12373P16473Thyrotropin receptorTier 1✓
CTLA4HGNC:2505P16410Cytotoxic T-lymphocyte protein 4Tier 2✓
PTPN22HGNC:9652Q9Y2R2Tyrosine-protein phosphatase non-receptor type 22Tier 1✓
IL2RAHGNC:6008P01589Interleukin-2 receptor subunit alphaTier 4N
CD40HGNC:11919P25942TNF receptor superfamily member 5Tier 4N
FCRL3HGNC:18506Q96P31Fc receptor-like protein 3Tier 4N
GPR174HGNC:30245Q9BXC1G-protein coupled receptor 174Tier 4N
BACH2HGNC:14078Q9BYV9Transcription regulator protein BACH2Tier 4N
TGHGNC:11764P01266ThyroglobulinTier 4N
CCR6HGNC:1607P51684C-C chemokine receptor type 6Tier 4N
VAV3HGNC:12659Q9UKW4Guanine nucleotide exchange factor VAV3Tier 4N
SLAMF6HGNC:21392Q96DU3SLAM family member 6Tier 4N
STAT4HGNC:11365Q14765Signal transducer/transcription activator 4Tier 4N
ARID5BHGNC:17362Q14865AT-rich interactive domain 5BTier 4N
MAP3K7HGNC:6859O43318MAP kinase kinase kinase 7 (TAK1)Tier 4N
ABOHGNC:79P16442Histo-blood group ABO transferaseTier 4N
RHOHHGNC:686Q15669Ras homolog family member HTier 4N
LPPHGNC:6679Q93052LIM domain containing preferred translocation partnerTier 4N
UBASH3AHGNC:15453P57075Ubiquitin-associated and SH3 domain-containing protein ATier 4N
ALDH2HGNC:404P05091Aldehyde dehydrogenase 2Tier 4N

Section 6: Protein Family Classification

Druggability by InterPro Family

Family TypeCountPercentageDruggable?Key Proteins
GPCRs37%✓ HIGHTSHR, GPR174, CCR6
Kinases12%✓ HIGHMAP3K7 (TAK1)
Phosphatases12%✓ MODERATEPTPN22
Cytokine receptors25%✓ MODERATEIL2RA, CD40
Ig-domain proteins37%✓ MODERATECTLA4, FCRL3
Enzymes (other)37%✓ MODERATEALDH2, ABO
Transcription factors37%DIFFICULTBACH2, STAT4, ARID5B
Scaffold/adaptor410%DIFFICULTVAV3, LPP, SLAMF6
Other/Unknown2151%VARIABLEVarious
Detailed Protein Family Table
GeneUniProtInterPro FamilyDruggable?Notes
TSHRP16473GPCR (Rhodopsin family)✓ HIGHPrimary disease target
GPR174Q9BXC1GPCR (Rhodopsin family)✓ HIGHOrphan GPCR
CCR6P51684GPCR (Chemokine receptor)✓ HIGHHas approved drug
MAP3K7O43318Protein kinase✓ HIGHMultiple approved kinase inhibitors
PTPN22Q9Y2R2Protein tyrosine phosphataseMODERATEPreclinical compounds
CTLA4P16410Ig V-set domain✓ HIGHMultiple approved biologics
IL2RAP01589Cytokine receptor (Sushi domain)✓ HIGHApproved biologics
CD40P25942TNF receptor superfamilyMODERATEClinical-stage antibodies
BACH2Q9BYV9BTB/bZIP transcription factorDIFFICULTNo ligand-binding pocket
STAT4Q14765STAT transcription factorDIFFICULTPPI target
Summary:
  • Highly druggable: 12 genes (29%)
  • Moderately druggable: 8 genes (20%)
  • Difficult targets: 10 genes (24%)
  • Unknown/Variable: 11 genes (27%)

Section 7: Expression Context

Bgee Expression Data for Key GWAS Genes

GeneTissuesExpression BreadthMax ScoreDisease Relevance
TSHRThyroid (high), adiposeUbiquitous99.28✓ Primary target organ
CTLA4Lymphoid tissues, T cellsUbiquitous87.62✓ Immune regulation
PTPN22Lymphoid, hematopoieticUbiquitous90.90✓ T cell signaling
IL2RAT cells, TregsUbiquitous81.96✓ Immune regulation
TGThyroid (specific)RestrictedHigh✓ Autoantigen
CD40B cells, dendritic cellsUbiquitousModerate✓ B cell activation
Disease-Relevant Expression Analysis:
  • Thyroid: TSHR, TG (autoantigen targets)
  • Immune cells (T/B/DC): CTLA4, PTPN22, IL2RA, CD40, FCRL3, SLAMF6
  • Ubiquitous: Most GWAS genes have broad expression

Tissue Specificity Assessment:

  • TSHR and TG show thyroid-enriched expression → favorable for targeting
  • Immune checkpoint genes (CTLA4, IL2RA) expressed on activated T cells → targeting may affect systemic immunity

Section 8: Protein Interactions

STRING Interaction Network Summary

ProteinInteraction PartnersHub ScoreKey Interactors
CTLA43,692Very HighCD28, CD80, CD86, B7 family
MAP3K74,434Very HighTAB1, TAB2, TRAF6, MKK pathway
IL2RAHighHighIL2, IL2RB, IL2RG, JAK/STAT
TSHR1,522HighTSH, Gs proteins, thyroid pathway
PTPN22ModerateModerateCSK, LCK, ZAP70, TCR signaling
Undrugged GWAS Genes with Drugged Interactors
Undrugged GeneInteracts WithDrugged InteractorApproved Drugs
BACH2PTPN22Yes (preclinical)-
FCRL3PTPN22, TSHRYesThionamides
SLAMF6CD28/CTLA4 pathwayYesAbatacept, Ipilimumab
VAV3TCR signalingMultipleKinase inhibitors
STAT4JAK1/JAK2YesRuxolitinib, Tofacitinib
Key Finding: STAT4 interacts with JAK kinases → JAK inhibitors may indirectly modulate this pathway

Section 9: Structural Data

PDB Structure Availability

ProteinPDB CountBest ResolutionStructure TypeAlphaFold
CTLA4221.64 ÅX-ray + Cryo-EM✓
TSHR91.9 ÅX-ray + Cryo-EM✓
PTPN22141.76 ÅX-ray✓
IL2RA101.83 ÅX-ray + Cryo-EM✓
MAP3K725VariableX-ray✓
CD4014VariableX-ray✓
BACH22LimitedX-ray✓
Structure Summary:
  • With experimental structure: 15 genes (37%)
  • AlphaFold only: 20 genes (49%)
  • Limited/no structure: 6 genes (14%)

Key Structural Insights

  • TSHR: Cryo-EM structures with TSH, autoantibodies (M22, K1-70), small molecule antagonists
  • CTLA4: Crystal structures with Ipilimumab, Tremelimumab, B7 ligands
  • PTPN22: Multiple structures with fragment hits at non-orthosteric sites (new druggability approach)

Section 10: Drug Target Analysis

Drugs Approved for Graves Disease (MeSH D006111)

DrugChEMBL IDTypePhaseMechanism
MethimazoleCHEMBL1515Small molecule4Thyroid peroxidase inhibitor
PropylthiouracilCHEMBL1518Small molecule4Thyroid peroxidase inhibitor
Potassium iodideCHEMBL1141Small molecule4Thyroid hormone synthesis
LevothyroxineCHEMBL1624Small molecule4Thyroid hormone replacement
PrednisoloneCHEMBL131Small molecule4Immunosuppressant
DexamethasoneCHEMBL384467Small molecule4Immunosuppressant
RituximabCHEMBL1201576Antibody4Anti-CD20
MycophenolateCHEMBL1456Small molecule4Immunosuppressant
Thyrotropin alfaCHEMBL1201533Protein4TSH analog (diagnostic)
CholestyramineCHEMBL1201625Other4Bile acid sequestrant
BatoclimabCHEMBL4650514Antibody3Anti-FcRn
GWAS Genes as Drug Targets
CategoryCountPercentageGenes
Approved drugs (Phase 4)820%CTLA4, IL2RA, MAP3K7, CCR6, ALDH2
Phase 3 drugs37%MAP3K7, CD40
Phase 1-2 drugs512%PTPN22, TSHR, CD40
Tool compounds only1024%GPR174, FCRL3, BACH2
No drug development1537%SLAMF6, VAV3, ARID5B, LPP
GWAS Genes with Approved Drugs (for OTHER Diseases)
GeneProteinDrugsApproved ForGraves-specific?
CTLA4P16410AbataceptRA, psoriatic arthritisN (repurposing opportunity)
CTLA4P16410IpilimumabMelanomaN
CTLA4P16410TremelimumabHCCN
IL2RAP01589BasiliximabTransplant rejectionN (repurposing opportunity)
IL2RAP01589DaclizumabMS (withdrawn)N
MAP3K7O43318SorafenibHCC, RCCN
MAP3K7O43318RuxolitinibMyelofibrosisN
CCR6P51684TegaserodIBSN
CD40P25942LucatumumabClinical trialsN
CD40P25942DacetuzumabClinical trialsN

Section 11: Bioactivity & Enzyme Data

PubChem Bioactivity Summary

ProteinUniProtAssay CountActive CompoundsNotes
TSHRP16473301 active (EC50 6.5 µM)Limited small molecule activity
MAP3K7O43318371ManyMultiple kinase inhibitors
PTPN22Q9Y2R2MultiplePreclinicalFragment-based hits
IL2RAP01589LimitedBiologics focusAntibody-dominated
ChEMBL Activity Data
ProteinChEMBL ActivitiesDevelopment StatusDruggable?
TSHR28,887Small molecules + antibodies✓
MAP3K7511Approved kinase inhibitors✓
PTPN22>200Preclinical phosphatase inhibitors✓
CTLA4Limited SMApproved antibodies✓
Enzyme-Specific Notes:
  • ALDH2: Well-characterized enzyme with Disulfiram interaction
  • PTPN22: New fragment-based approaches targeting non-orthosteric sites

Section 12: Pharmacogenomics

PharmGKB Annotations for GWAS Genes

GenePharmGKB IDDrug InteractionsClinical Annotations
TSHRPA37042ThionamidesThyroid drug response
CTLA4PA27006ImmunomodulatorsAutoimmune drug response
PTPN22PA33995Autoimmune drugsDisease susceptibility
IL2RAPA29828ImmunosuppressantsTransplant/MS drugs
Key Variant-Drug Associations
VariantGeneDrugsClinical Impact
rs2476601PTPN22Multiple autoimmune drugsDisease susceptibility modifier
rs3087243CTLA4ImmunomodulatorsResponse variability

Section 13: Clinical Trials

Total Graves Disease Trials: 203

Trials by Phase

PhaseCountPercentage
Phase 4147%
Phase 3115%
Phase 2147%
Phase 194%
Observational/Other15577%
TOP 30 Drugs in Clinical Trials
DrugPhaseMechanismTargetGWAS Gene?
Methimazole4TPO inhibitorTPON
Propranolol4Beta-blockerADRBN
Prednisolone4CorticosteroidGRN
Methylprednisolone4CorticosteroidGRN
Radioiodine (I-131)4AblativeThyroidN
Levothyroxine4Hormone replacementTSHR✓ Partial
Rituximab4Anti-CD20CD20N
Batoclimab2Anti-FcRnFcRnN
K1-701Anti-TSHR antibodyTSHR✓
ATX-GD-591TolerogenMultipleN
CFZ5332Anti-CD40CD40✓
Rilzabrutinib2BTK inhibitorBTKN
IMVT-14022Anti-FcRnFcRnN
CAR-T (anti-CD19)EarlyCell therapyCD19N
GWAS-Target Alignment: ~15% of trial drugs target GWAS genes (moderate alignment)

Section 14: Pathway Analysis

Reactome Pathway Enrichment

PathwayIDGWAS GenesDruggable Nodes
Co-inhibition by CTLA4R-HSA-3895132CTLA4 ✓
Co-stimulation by CD28R-HSA-3893562CD28, CTLA4 ✓
TCR signalingR-HSA-2024273PTPN22, ZAP70 ✓
Interleukin-2 signalingR-HSA-90205582IL2RA, JAK ✓
Treg development (RUNX1/FOXP3)R-HSA-88773302CTLA4, IL2RA
G alpha (s) signallingR-HSA-4185551TSHR ✓
Hormone receptor bindingR-HSA-3752811TSHR
Pathway-Level Druggability
PathwayDruggable Entry PointsAvailable Drugs
T cell co-inhibitionCTLA4Abatacept, Ipilimumab
IL-2/IL-2R signalingIL2RA, JAK1/2Basiliximab, Ruxolitinib
TCR signalingPTPN22, LCK, ZAP70Preclinical compounds
TSH/TSHR axisTSHRThionamides (indirect), K1-70

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates (Prioritized)

RankDrugTarget GeneApproved ForGWAS P-valueFamilyPriority
1AbataceptCTLA4RA, JIA4×10⁻²⁶Ig fusion★★★★★
2BasiliximabIL2RATransplant2×10⁻⁶Antibody★★★★☆
3RuxolitinibMAP3K7/JAKMyelofibrosis-Kinase inh★★★★☆
4TofacitinibJAK pathwayRA-JAK inh★★★★☆
5BaricitinibJAK pathwayRA, COVID-JAK inh★★★★☆
6TegaserodCCR6IBS7×10⁻¹⁰GPCR★★★☆☆
7SorafenibMAP3K7HCC, RCC-Multi-kinase★★☆☆☆
8SunitinibMAP3K7RCC, GIST-Multi-kinase★★☆☆☆
9DisulfiramALDH2Alcoholism3×10⁻¹⁵Enzyme inh★★☆☆☆
Repurposing Rationale

Tier 1 - Strong Evidence (Abatacept):

  • CTLA4 is top GWAS hit (p=4×10⁻²⁶)
  • Mendelian overlap (CTLA4 haploinsufficiency)
  • Approved for multiple autoimmune diseases
  • Mechanism: blocks T cell co-stimulation
  • Recommendation: High priority for clinical trial

Tier 2 - Moderate Evidence (IL2RA targeting):

  • IL2RA is established GWAS hit
  • Basiliximab approved for transplant rejection
  • Tregs express high IL2RA → may affect regulatory pathways
  • Consideration: Balance efficacy vs Treg depletion

Tier 3 - Pathway-Based (JAK inhibitors):

  • STAT4 interacts with JAK pathway
  • IL2 signaling uses JAK1/JAK3
  • Multiple approved JAK inhibitors
  • Recommendation: Consider for refractory cases

Section 16: Druggability Pyramid

LevelDescriptionCount%Key Genes
Level 1VALIDATED: Approved drug FOR Graves00%None (current drugs don't target GWAS genes)
Level 2REPURPOSING: Approved for OTHER disease820%CTLA4, IL2RA, MAP3K7, CCR6, ALDH2
Level 3EMERGING: Drug in clinical trials410%TSHR (K1-70), CD40 (CFZ533)
Level 4TOOL COMPOUNDS: ChEMBL but no trials820%PTPN22, GPR174, FCRL3
Level 5DRUGGABLE UNDRUGGED: Family but no compounds615%STAT4, BACH2 (TF)
Level 6HARD TARGETS: Difficult/unknown1535%SLAMF6, VAV3, LPP, ARID5B
Pyramid Visualization
[L1[L2[L3[L4[L5[L6Key Insight
0%] VALIDATED
20% - 8 genes] REPURPOSING READY
10% - 4 genes] EMERGING (TRIALS)
20% - 8 genes] TOOL COMPOUNDS EXIST
15% - 6 genes] DRUGGABLE BUT UNDRUGGED
35% - 15 genes] HARD TARGETS / UNKNOWN
30% of GWAS genes (Levels 2-3) have immediate repurposing/clinical potential, while 35% require new modality development.

Section 17: Undrugged Target Profiles

TOP 10 High-Value Undrugged Targets

  1. GPR174 (X chromosome)
AttributeValue
GWAS P-value8×10⁻²²
ProteinQ9BXC1
FamilyGPCR (Rhodopsin)
StructureAlphaFold
ExpressionImmune cells
InteractionsLimited
Why UndruggedOrphan GPCR, no known ligand
DruggabilityHIGH - GPCR family
  1. SLAMF6 (chr 1)
AttributeValue
GWAS P-value3×10⁻¹³
ProteinQ96DU3
FamilyIg superfamily
StructureLimited
ExpressionT cells, NK cells
InteractionsSLAM pathway
Why UndruggedPPI target, no small molecule pocket
DruggabilityMEDIUM - Antibody possible
  1. BACH2 (chr 6)
AttributeValue
GWAS P-value7×10⁻⁹
ProteinQ9BYV9
FamilyTranscription factor (bZIP)
StructurePartial (2 PDB)
ExpressionB cells, T cells
InteractionsTreg development
Why UndruggedTF - no ligand-binding domain
DruggabilityLOW - Difficult TF target
  1. UBASH3A (chr 21)
AttributeValue
GWAS P-value7×10⁻¹⁰
ProteinP57075
FamilyPhosphatase (UBASH3)
StructureAlphaFold
ExpressionT cells
InteractionsTCR signaling
Why UndruggedNovel target, limited tool compounds
DruggabilityMEDIUM - Phosphatase family
  1. FCRL3 (chr 1)
AttributeValue
GWAS P-value2×10⁻¹³
ProteinQ96P31
FamilyFc receptor-like (Ig domain)
StructureAlphaFold
ExpressionB cells
InteractionsB cell regulation
Why UndruggedNo validated ligand
DruggabilityMEDIUM - Antibody target
  1. VAV3 (chr 1)
AttributeValue
GWAS P-value4×10⁻⁸
ProteinQ9UKW4
FamilyGEF (DH-PH domain)
StructurePartial
ExpressionHematopoietic
InteractionsRac signaling
Why UndruggedPPI interface, allosteric modulation needed
DruggabilityLOW - GEF difficult target
  1. LPP (chr 3)
AttributeValue
GWAS P-value4×10⁻¹³
ProteinQ93052
FamilyLIM domain protein
StructureLimited
ExpressionUbiquitous
InteractionsCell adhesion
Why UndruggedScaffold protein, no enzymatic activity
DruggabilityLOW - Scaffold protein
  1. ARID5B (chr 10)
AttributeValue
GWAS P-value1×10⁻¹¹
ProteinQ14865
FamilyARID transcription factor
StructureAlphaFold
ExpressionUbiquitous
InteractionsChromatin regulation
Why UndruggedTF with DNA-binding domain
DruggabilityLOW - TF target
Undrugged Target Summary
DruggabilityCountGenes
HIGH2GPR174
MEDIUM4SLAMF6, UBASH3A, FCRL3
LOW9BACH2, VAV3, LPP, ARID5B, others

Section 18: Summary

GWAS LANDSCAPE

MetricValue
Total associations134
Unique studies23
Unique genes41
Coding variants7%
Non-coding variants93%
GENETIC EVIDENCE
MetricValue
Tier 1 (coding) genes3 (PTPN22, TSHR)
Mendelian overlap3 genes (TSHR, CTLA4, PTPN22)
Both criteria3 genes
DRUGGABILITY
MetricValue
Overall druggable rate50% have drug-relevant targets
With approved drugs20% (8 genes)
In clinical trials10% (4 genes)
Opportunity gap (undrugged)35% (15 genes)
PYRAMID SUMMARY
LevelCount%
L1 - Validated00%
L2 - Repurposing820%
L3 - Emerging410%
L4 - Tool compounds820%
L5 - Druggable undrugged615%
L6 - Hard targets1535%
CLINICAL TRIAL ALIGNMENT
  • ~15% of current trial drugs target GWAS genes
  • Gap between genetic evidence and therapeutic development
  • K1-70 (anti-TSHR) and CFZ533 (anti-CD40) represent genetically-informed approaches

TOP 10 REPURPOSING CANDIDATES

RankDrug → GeneApproved ForP-valueScore
1Abatacept → CTLA4RA4×10⁻²⁶★★★★★
2Basiliximab → IL2RATransplant2×10⁻⁶★★★★☆
3Ruxolitinib → JAK/STAT4MFpathway★★★★☆
4Tofacitinib → JAKRApathway★★★★☆
5Baricitinib → JAKRApathway★★★☆☆
6Tegaserod → CCR6IBS7×10⁻¹⁰★★★☆☆
7Upadacitinib → JAKRApathway★★★☆☆
8Filgotinib → JAKRApathway★★★☆☆
9Sorafenib → MAP3K7HCCindirect★★☆☆☆
10Disulfiram → ALDH2Alcohol3×10⁻¹⁵★★☆☆☆
TOP 10 UNDRUGGED OPPORTUNITIES
GeneP-valueFamilyStructurePotential
GPR1748×10⁻²²GPCRAlphaFoldHIGH
FCRL32×10⁻¹³Ig-likeAlphaFoldMEDIUM
SLAMF63×10⁻¹³SLAMLimitedMEDIUM
UBASH3A7×10⁻¹⁰PhosphataseAlphaFoldMEDIUM
BACH27×10⁻⁹TF (bZIP)PartialLOW
VAV34×10⁻⁸GEFPartialLOW
LPP4×10⁻¹³LIM domainLimitedLOW
ARID5B1×10⁻¹¹TF (ARID)AlphaFoldLOW
TOP 10 INDIRECT OPPORTUNITIES
Undrugged GeneDrugged InteractorDrug
STAT4JAK1/JAK2Ruxolitinib, Tofacitinib
BACH2Treg pathwayIL-2 mutein therapies
FCRL3BCR signalingBTK inhibitors
SLAMF6CD28/CTLA4Abatacept
VAV3Rac/TCRPreclinical compounds
KEY INSIGHTS
  1. HLA-centric architecture: Most significant signals in HLA region (chr 6), consistent with autoimmune etiology
  2. Immune checkpoint druggability: CTLA4 (top GWAS hit) already has approved drugs for other autoimmune diseases → Abatacept is prime repurposing candidate
  3. TSHR as therapeutic target: The disease-defining autoantigen (TSHR) is a GWAS hit with emerging therapeutics (K1-70 blocking antibody)
  4. JAK pathway convergence: Multiple GWAS genes (IL2RA, STAT4) connect to JAK signaling → JAK inhibitors represent pathway-based opportunity

5. Undrugged GPCR opportunity: GPR174 is an orphan GPCR with strong GWAS signal (p=8×10⁻²²) - high priority for ligand discovery

  1. Trial-genetics gap: Only ~15% of clinical trial drugs target GWAS genes, indicating disconnect between genetic evidence and drug development
  2. Transcription factor challenge: Multiple TF hits (BACH2, STAT4, ARID5B) are difficult to drug directly - require pathway approaches
  3. Comparison to other autoimmune diseases: Similar genetic architecture to Type 1 diabetes, RA, and other autoimmune conditions - supports class-wide repurposing strategies

Analysis Complete

This comprehensive GWAS-to-drug-target druggability analysis for Graves Disease reveals:

Key Findings:

  • 134 GWAS associations across 23 studies mapping to 41 protein-coding genes
  • Top repurposing candidate: Abatacept (CTLA4-Ig fusion) - already approved for RA, targets the #2 GWAS gene
  • Highest-priority undrugged target: GPR174 (orphan GPCR, p=8×10⁻²²)
  • 20% of GWAS genes have approved drugs for other diseases (repurposing ready)
  • 35% remain “hard targets” (TFs, scaffold proteins)

Immediate Opportunities:

  1. Abatacept clinical trial for Graves disease (strong genetic rationale)
  2. JAK inhibitors (Ruxolitinib, Tofacitinib) via STAT4/IL2RA pathway
  3. GPR174 ligand discovery - high-value orphan GPCR

Notable Gap: Only ~15% of current Graves disease trial drugs target GWAS-validated genes, indicating significant opportunity to align drug development with genetic evidence.